Primary Sjogren's syndrome (pSS) is a systemic chronic inflammatory autoimmune disease characterized by dry eyes and dry mouth. Essential histopathologic features of pSS include focal infiltrations of T and B cells in the salivary and lacrimal glands that lead to tissue injury and chronic inflammation. In some cases, the histopathologic changes develop into tertiary lymphoid tissues or organs (TLs) via a process called lymphoid neogenesis. TLOs resemble spleen and lymph nodes in their cellular composition and organization. TLOs may serve as a place where recruitment of T cells with lymphoid homing capacity (naive and central memory cells) as well as their activation, proliferation and differentiation occur. CD4+ T cells that orchestrate immune responses can be divided into T-helper (Th)1, Th2 and Th17 cells as well as CD4+ T cells with regulatory function including forkhead box P3 (FOXP3)-positive regulatory T cells (Treg). Although T cells and their cytokines are found in the salivary tissues of pSS, it is unknown which type of T cells has a leading role in the pathogenesis. This project investigates the hypothesis that patients with pSS have an altered balance of Th17 and Treg immune responses that is caused by chronic inflammation with lymphoid neogenesis and defect(s) in differentiating and functioning of Th17 cells and Treg based on the facts that Th17 cells potently induce inflammation while Treg suppress it. Plus, the both cell types are linked with autoimmunity and have a reciprocal relationship in cellular differentiation under inflammatory milieu. The hypothesis will be addressed with: 1) Aim 1. Determine if the TLOs in pSS could serve as sites of antigen presentation for induction of autoantibodies, tolerance or activation, focusing on Treg and Th17 cells; 2) Aim 2. Determine if patients with pSS have an altered balance of Th17 and Treg immune responses in the peripheral blood secondary to a defect(s) in Th17 cells and Treg differentiation and function; and 3) Aim 3. Determine if the altered balance of Th17 and Treg immune responses in peripheral blood correlates with TLOs in the fresh minor salivary tissues in patients with pSS. These studies will shed new light on the pathogenesis and treatment of autoimmune diseases including pSS.